Thienopyridine derivative for the treatment of hepatitis C infections

ABSTRACT

The present invention relates to methods of treatment of hepatitis C using prasugrel. The methods of the present invention can be used in patients with hepatitis C administering prasugrel in combination with one or more anti-hepatitis C drugs.

CROSS REFERENCE TO RELATED APPLICATION

This application is a continuation of U.S. application Ser. No.15/212,703, filed Jul. 18, 2016, which claims the benefit of IndianApplication 2691/MUM/2015, filed Jul. 16, 2015, the contents of whichare hereby incorporated in their entirety.

FIELD OF THE INVENTION

The present invention relates to method of treating Hepatitis C byadministering a thienopyridine derivative alone or optionally incombination with one or more anti-hepatitis C drugs to a subject in needthereof. In particular, the present invention pertains to methods forthe treatment of Hepatitis C viral infection in humans by administeringPrasugrel alone or in combination with one or more anti-Hepatitis Cdrugs.

BACKGROUND

HCV (Hepatitis C virus) is a major cause of chronic liver disease.Hepatitis C virus is most commonly transmitted through exposure tocontaminated blood. Due its widespread nature and global burden, thisdisease has always attracted attention for insight into its causativeagent hepatitis C virus (HCV) and for the development of new therapeuticapproaches. Even after twenty-four years from its discovery, HCVcontinues to be a major cause of concern and a huge burden on publichealth systems worldwide. WHO estimates that a minimum of 3% of theworld's population is chronically infected with HCV. As cited in variousresearch articles, HCV has caused massive impact on public health, andaround 180 million people in the world are infected with HCV, with anestimated 3 to 4 million new infections global per year. It causesinfection in two phases, first involves acute attack that last for fewweeks; if untreated HCV may persist for long time which is termed aschronic hepatitis C. This chronic infection may often lead to chronicliver disease (CLD) that may ultimately lead to hepatic failure andhepato-cellular carcinoma.

The HCV virion is an enveloped positive-strand RNA virus with a singleoligoribonucleotide genomic sequence of about 9600 bases which encodes apolyprotein of about 3,010 amino acids. The protein products of the HCVgene consist of the structural proteins C, E1, and E2, and thenon-structural proteins NS2, NS3, NS4A and NS4B, and NS5A and NS5B.

The main targets of the direct-acting antiviral agents are theHCV-encoded proteins that are vital to the replication of the virus. Theinfectious viral structure is comprised of envelope glycoproteins in alipid bilayer that contain the viral core protein and RNA. After cellentry, the viral RNA is translated through host machinery into apolyprotein, which is cleaved during and after translation by both hostand viral-encoded proteases into 10 mature viral proteins, including anumber of nonstructural (NS) proteins. One of the viral proteasesinvolved in this post-translational processing is a heterodimericcomplex of the NS3 and NS4A proteins (NS3/NS4A). NS3 possesses theproteolytic activity and NS4 is a membrane protein that acts as acofactor. Synthesis of new viral RNA occurs in a highly structuredreplication complex that consists of NS3, NS4A, NS4B, NS5A, and NS5B.NS5B is an RNA-dependent RNA polymerase that is essential for viralreplication. NS5A has a presumptive role in the organization of thereplication complex and in regulating replication. It is also involvedin assembly of the viral particle that is released from the host cell.Direct-acting antivirals are inhibitors of the NS3/4A protease, the NS5Aprotein, and the NS5B polymerase.

HCV is characterized by an extremely high degree of variability. Thegenetic heterogeneity of HCV leads to multiple genomic variants allowingrapid selection of mutants that better adapts to environmental changes.This genetic heterogeneity is the basis of chronic infection which leadsto limited treatment efficacy. The various available options for thetreatment of hepatitis C are screening, surgery, liver transplant,radiation therapy, chemotherapy, virus therapy and targeted therapy. Anumber of potential molecular targets for drug development ofdirect-acting antivirals (DAAs) as anti-HCV therapeutics have now beenidentified including, but not limited to, the NS2-NS3 autoprotease, NS4Aprotease, the N3 protease, the N3 helicase, and the NS5B polymerase.

Currently approved standard of care (“SOC”) for the treatment of chronicHCV infection is a combination therapy with pegylated interferon alfa-2aor pegylated interferon alfa-2b (collectively “peginterferon” or “PEG”)used alone or in combination with ribavirin (“RBV”). Other FDA approveddrugs for hepatitis C include Olysio® (simeprevir), Victrelis®(boceprevir), Sovaldi® (sofosbuvir), Epclusa (Sofosbuvir; Velpatasvir)®,Viekirax® (dasabuvir, ombitasvir, paritaprevir, ritonavir), Daklinza®(daclatasavir), Exviera® (dasabuvir), Harvoni® (Ledipasvir Sofosbuvir),Incivek® (telaprevir), Technivie® (ombitasvir; paritaprevir; ritonavir)Zepatier® (elbasvir; grazoprevir), Viekira Pak® (dasabuvir sodium;ombitasvir; paritaprevir; ritonavir) etc.

Challenges facing current treatment of HCV include lack of efficacy inpatients with difficult-to-treat disease, such as patients withcirrhosis or infected with HCV genotype 1 (who represent a majority ofUS HCV infections), the toxicity of combination therapy, the difficultyof therapy, and the poor reception of these treatments by many patients.Moreover an attempt to invent new drugs for the treatment of HCV wouldbe costly and time consuming. Thus, there is a need for new treatmentsand therapies for HCV infection to treat or ameliorate one or moresymptoms of Hepatitis C. Accordingly, the current invention focuses onthe existing pool of drugs which could be effective in the treatment ofHepatitis C with the ultimate goals of targeting the virus, viralresistance challenges, shortening the length of therapy, improvingsustained virologic response rates, and minimizing side effects.

SUMMARY OF THE INVENTION

According to one aspect of the present invention, there is provided amethod of treating Hepatitis C comprising administering a thienopyridinederivative wherein the thienopyridine derivative is prasugrel.

According to yet another aspect of the present invention, there isprovided a method of alleviating or treating Hepatitis C byadministration of prasugrel in combination with one or moreanti-hepatitis C drugs.

According to yet another aspect of the invention, there is provided apharmaceutical composition comprising prasugrel for the treatment ofHepatitis C.

According to another aspect of the present invention, there is provideda pharmaceutical composition comprising prasugrel in combination withone or more anti-hepatitis C drugs.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 includes a graph of Prasugrel in HCV GT1b CON-1 replicon assay.

FIG. 2 includes a graph of Prasugrel in HCVcc assay

DETAILED DESCRIPTION OF THE INVENTION

Hepatitis C is a complex disease of the liver. Due its widespread natureand global burden, this disease has always attracted attention forinsight into its causative agent, hepatitis C virus (HCV), and for thedevelopment of new therapeutic approaches. Despite years of discovery,HCV continues to be a major cause of concern and a huge burden on publichealth systems worldwide.

The present invention contemplates the use of a pharmaceutical agent forthe treatment of viral infection hepatitis C. In one embodiment, thepharmaceutical agent is a thienopyridine derivative. In one embodiment,the pharmaceutical agent is prasugrel.

Prasugrel was first disclosed in U.S. Pat. No. 5,288,726, and belongs tothe class of thienopyridine adenosine diphosphate receptor antagonists.It is chemically designated as5-[(1RS)-2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-ylacetate hydrochloride. It is sold in the United States as thehydrochloride salt under the name Effient®. The chemical structure ofprasugrel hydrochloride is:

Prasugrel is an inhibitor of platelet activation and aggregation throughthe irreversible binding of its active metabolite to the P2Y12 class ofADP receptors on platelets. It reduces the aggregation (“clumping”) ofplatelets by irreversibly binding to P2Y12 receptors.

Effient® indicated to reduce the rate of thrombotic cardiovascular (CV)events (including stent thrombosis) in patients with acute coronarysyndrome (ACS) who are to be managed with percutaneous coronaryintervention (PCI)-patients with unstable angina (UA) ornon-ST-elevation myocardial infarction (NSTEMI), patients withST-elevation myocardial infarction (STEMI) when managed with primary ordelayed PCI.

Effient® is available in 5 mg and 10 mg tablets. Effient® 5-mg isavailable as a yellow, elongated hexagonal, film-coated, non-scoredtablet and Effient® 10-mg is available as a beige, elongated hexagonal,film-coated, non-scored tablet. Initial dose of Effient® is with 60-mgoral loading doe and continue at 10-mg once daily with or without food.Consider 5-mg once daily for patients <60 kg. Patients are recommendedto take aspirin (75-mg to 325-mg) daily. Prasugrel has been shown toreduce the rate of a combined endpoint of cardiovascular death, nonfatalmyocardial infarction (MI), or nonfatal stroke compared to clopidogrel.It is generally recommended that antiplatelet therapy be administeredpromptly in the management of ACS because many cardiovascular eventsoccur within hours of initial presentation.

Numerous methods of identifying the presence of Hepatitis C in patientsor biological samples have been developed. These include, but are notlimited to the compositions of matter, devices and methods as set forthin U.S. Pat. Nos. 5,580,718; 5,574,132; 5,597,691; 5,552,310; 5,514,539;and 5,595,868.

The inventors of the present invention have found that prasugrel hasactivity for the treatment of hepatitis C. Viral infections coincidewith platelet activation, and a host's inflammatory response results inthe release of platelet activating mediators and a pro-oxidative and apro-coagulant environment which favors platelet activation. Thus,platelet activation not only occurs in response to injury, but alsomodulates host response and viral survival. Hence platelet activationinhibition is a promising approach for anti-viral therapy. Prasugrel, isan inhibitor of platelet activation and aggregation through theirreversible binding of its active metabolite to the P2Y12 class of ADPreceptors on platelets, can modulate viral infection.

Treatment with prasugrel offers several advantages over other treatmentschemes (e.g., interferon). Unlike interferon, prasugrel is potentiallyimproving patient safety and compliance. Prasugrel is fairly welltolerated with few side effects, and is cost effective. Thus prasugrelmay result in higher compliance with hepatitis C patients, improvingoverall outcomes.

The term “combination” as used herein, defines either a fixedcombination in one dosage unit form, a non-fixed combination or a kitcontaining individual parts for combined administration.

The term “treating” or “treatment” as used herein comprises a treatmentrelieving, reducing or alleviating at least one symptom in a subject oreffecting a delay of progression of a disease. For example, treatmentcan be the diminishment of one or several symptoms of a disorder orcomplete eradication of a hepatitis C virus including viral resistance.Within the meaning of the present invention, the term “treat” alsoincludes to arrest, delay the onset (i.e., the period prior to clinicalmanifestation of a disease) and/or reduce the risk of developing orworsening a disease.

The term “prasugrel” is used in broad sense to include not only“prasugrel” per se but also its pharmaceutically acceptable derivativesthereof. Suitable pharmaceutically acceptable derivatives includepharmaceutically acceptable salts, pharmaceutically acceptable solvates,pharmaceutically acceptable hydrates, pharmaceutically acceptableanhydrates, and pharmaceutically acceptable polymorphs.

Pharmaceutically acceptable salts are salts that retain the desiredbiological activity of the parent compound and do not impart undesirabletoxicological effects. Examples of such salts are acid addition saltsformed with inorganic acids, for example, hydrochloric, hydrobromic,sulfuric, phosphoric, and nitric acids and the like; salts formed withorganic acids such as acetic, oxalic, tartaric, succinic, maleic,fumaric, gluconic, citric, malic, methanesulfonic, p-toluenesulfonic,napthalenesulfonic, and polygalacturonic acids, and the like; saltsformed from elemental anions such as chloride, bromide, and iodide;salts formed from metal hydroxides, for example, sodium hydroxide,potassium hydroxide, calcium hydroxide, lithium hydroxide, and magnesiumhydroxide; salts formed from metal carbonates, for example, sodiumcarbonate, potassium carbonate, calcium carbonate, and magnesiumcarbonate; salts formed from metal bicarbonates, for example, sodiumbicarbonate and potassium bicarbonate; salts formed from metal sulfates,for example, sodium sulfate and potassium sulfate; and salts formed frommetal nitrates, for example, sodium nitrate and potassium nitrate.Pharmaceutically acceptable and non-pharmaceutically acceptable saltsmay be prepared using procedures well known in the art, for example, byreacting a sufficiently basic compound such as an amine with a suitableacid comprising a physiologically acceptable anion. Alkali metal (forexample, sodium, potassium, or lithium) or alkaline earth metal (forexample, calcium) salts of carboxylic acids can also be made. In certainembodiment prasugrel is provided as the hydrochloride salt.

Depending on the pathological stage, patient's age and otherphysiological parameters, and the extent of invasion, prasugrel mayrequire specific dosage amounts and specific frequency ofadministrations. Preferably, prasugrel may be administered at leastonce, twice or thrice a day in an amount from 2 mg to 100 mg. In certainembodiments, the prasugrel is administered in a daily dose in an amountgreater than 10 mg day. In some embodiments, prasugrel may beadministered such that the total daily dose is in an amount from 5-100mg, 10-100 mg, 15-100 mg, 20-100 mg, 25-100 mg, 30-100 mg, 35-100 mg,40-100 mg, 45-100 mg, 50-100 mg, 10-50 mg, 15-50 mg, 20-50 mg, 25-50 mg,30-50 mg, 35-50 mg, 40-50 mg, 10-25 mg, or 15-25 mg. In certainembodiments, prasugrel is administered in an amount that the total dailydose is greater than 10 mg. When prasugrel is administered as apharmaceutically acceptable salt, the dose levels refer the equivalentamount of prasugrel free base. For instance, a dose level of 5 mg ofprasugrel corresponds to 5.49 mg of prasugrel hydrochloride.

In some embodiments, prasugrel may be administered to a hepatitis Cpatient for a period of at least 2 weeks, at least 4 weeks, at least 6weeks, at least 10 weeks, at least 12 weeks, at least 15 weeks, at least20 weeks, at least 30 weeks, at least 40 weeks, or at least 52 weeks. Insome instances, prasugrel may be administered for a period of 2-52weeks, 2-104 weeks, or 2-208 weeks.

Preferably, prasugrel may be provided in the form of a pharmaceuticalcomposition such as but not limited to, unit dosage forms includingtablets, capsules (filled with powders, pellets, beads, mini-tablets,pills, micro-pellets, small tablet units, multiple unit pellet systems(MUPS), disintegrating tablets, dispersible tablets, granules, andmicrospheres, multiparticulates), sachets (filled with powders, pellets,beads, mini-tablets, pills, micro-pellets, small tablet units, MUPS,disintegrating tablets, dispersible tablets, granules, and microspheres,multiparticulates), powders for reconstitution and sprinkles,transdermal patches, however, other dosage forms such as controlledrelease formulations, lyophilized formulations, modified releaseformulations, delayed release formulations, extended releaseformulations, pulsatile release formulations, dual release formulationsand the like. Liquid and semisolid dosage forms (liquids, suspensions,solutions, dispersions, ointments, creams, emulsions, microemulsions,sprays, patches, spot-on), parenteral, topical, inhalation, buccal,nasal etc. may also be envisaged under the ambit of the invention.Dosage forms may be administered orally, or by injection (IV, SC, IM).

Prasugrel may be used for the treatment of Hepatitis C in mammals inmonotherapy mode or in a combination therapy (e.g., dual combination,triple combination etc.) mode such as, for example, in combination withone or more anti-hepatitis C drugs. In some instances, the prasugrel orcombination therapy can be administered to patients that are notundergoing or recovering from percutaneous coronary intervention. Insome embodiments, the hepatitis C patients do not have acute coronarysyndrome, unstable angina or ST-elevation myocardial infarction.

The inventors of the present invention have also found that thesolubility properties of prasugrel may be improved by nanosizing thusleading to better bioavailability and dose reduction of the drug.

In one embodiment, prasugrel may be present in the form of nanoparticleswhich have an average particle size of less than 2,000 nm, less than1,800 nm, 1,600 nm, less than 1,400 nm, less than 1,200 nm, or less than1,000 nm.

Suitable excipients may be used for formulating the dosage formaccording to the present invention such as, but not limited to, surfacestabilizers or surfactants, viscosity modifying agents, polymersincluding extended release polymers, stabilizers, disintegrants or superdisintegrants, diluents, plasticizers, binders, glidants, lubricants,sweeteners, flavoring agents, anti-caking agents, opacifiers,anti-microbial agents, antifoaming agents, emulsifiers, bufferingagents, coloring agents, carriers, fillers, anti-adherents, solvents,taste-masking agents, preservatives, antioxidants, texture enhancers,channeling agents, coating agents or combinations thereof.

There is provided a method of alleviating or treating hepatitis C byadministration of prasugrel optionally in combination with one or moreanti-hepatitis C drugs.

Preferably, one or more anti-hepatitis C drugs that may be envisagedunder the scope of the present invention may comprise from categories ofanti-hepatitis C drugs for the treatment of hepatitis C such as, but notlimited to, recombinant Human Interferon Alfa such as pegylatedinterferon alfa-2a or pegylated interferon alfa-2b (collectively“peginterferon” or “PEG”), nucleoside analogs for example ribavirin,direct acting antivirals (for example daclatasvir, boceprevir andtelapravir), NS3/4A protease inhibitors (PIs) (for example simeprevir),nucleotide NS5B polymerase pnhibitors (for example sofosbuvir), NS5AInhibitors (for example daclatasvir), non-nucleoside NS5B PolymeraseInhibitors (for example dasabuvir) or multi-class combination drugs (forexample sofosbuvir/velpatasvir, ledipasvir/sofosbuvir,ombitasvir/paritaprevir/ritonavir, ombitasvir/paritaprevir/ritonavir anddasabuvir, elbasvir/grazoprevir, daclatasvir/asunaprevir/beclabuvir).

The use of prasugrel may preferably be associated with one or more ofthe above referenced anti-hepatitis C drugs as a combination therapy(either of the same functional class or other) depending on variousfactors like drug-drug compatibility, patient compliance and other suchfactors wherein the said combination therapy may be administered eithersimultaneously, sequentially, or separately for the treatment ofhepatitis C.

Prasugrel may be provided with one or more anti-hepatitis drugs in theform of a kit, wherein the kit includes prasugrel and at least one otheranti-hepatitis C drug, and instructions for their administration to ahepatitis C patient.

According to the present invention there is provided a pharmaceuticalcomposition comprising prasugrel in combination with one or moreanti-hepatitis C drugs.

In certain embodiments, the administration of prasugrel, either alone orin combination with one or more anti-hepatitis drugs, can lowerdetectable HCV-RNA levels in a hepatitis patient. For instance, methodsdisclosed herein can lower HCV-RNA levels by at least 10%, at least 20%,at least 30%, at least 4%, at least 50%, at least 60%, at least 70%, atleast 80%, at least 90%, or at least 95% relative to HCV-RNA levelsprior to initiating treatment. In some instances, prasugrel can beadministered to a patient such no HCV-RNA is detectable in the patientafter the treatment course is complete. HCV-RNA levels can be determinedby quantitative, multi-cycle reverse transcriptase PCR. Such techniquesare known, for instance in U.S. Pat. No. 6,172,046, col. 4, line 50-col.6, line 5, which is hereby incorporated by reference. As used herein, nodetectable HCV-RNA describes a condition in which there are less than100 copies per ml serum of the patient.

It may be well appreciated by a person skilled in the art that thepharmaceutical composition comprising prasugrel in combination with oneor more anti-hepatitis C drugs may require specific dosage amounts andspecific frequency of administrations specifically considering theirindividual established doses, the dosing frequency, patient adherenceand the regimen adopted. As described herein, considering that there arevarious parameters to govern the dosage and administration of thecombination composition as per the present invention, it would be wellacknowledged by a person skilled in the art to exercise caution withrespect to the dosage, specifically, for special populations associatedwith other disorders.

In order that this invention be more fully understood, the followingpreparative and testing methods are set forth. These methods are for thepurpose of illustration only and are not to be construed as limiting thescope of the invention in any way.

EXAMPLES Example 1: HCV Replicon Assay

Stable HCV replicons of different genotypes may be used for anti-HCVevaluation. We use the subgenomic HCV replicons of genotype 1a (H77strain), 1b (Con1 strain), and 2a (JFH-1 strain), which are Huh7 humanhepatoma cell lines that contains an HCV replicon.

The HCV replicon antiviral evaluation assay examines the effects ofcompound at six serial dilutions. Human interferon alpha-2b (rIFNα-2b)and Sofosbuvir are included in each run as a positive control compound.

Briefly, the replicon cells are plated at 5,000 cells/well into 96-wellplates that are dedicated for the analysis of cell numbers(cytotoxicity) or antiviral activity. On the following day, samples arediluted with assay media and added to the appropriate wells. Cells areprocessed 72 hours later when the cells are still sub-confluent. For theluciferase endpoint assay, HCV replicon levels are assessed asreplicon-derived Luc activity. The concentration of drug that reducescell viability is assessed by the fluorometric CytoTox-1 cellproliferation assay (Promega), (expressed as cell numbers). For theqRT-PCR/TaqMan assay, total RNA is extracted from the replicon cellsusing RNeasy 96 kit (Qiagen) according to the manufacturer's protocol.Real-time RTPCR/TaqMan assays are performed to measure copy numbers ofthe replicon RNA and cellular ribosomal RNA. Where applicable EC₅₀(concentration inhibiting HCV replicon by 50%), EC₉₀ (concentrationinhibiting HCV replicon by 90%), CC₅₀ (concentration decreasing cellviability by 50%), CC₉₀ (concentration decreasing cell viability by 90%)and SI (selectivity indices: CC₅₀/EC₅₀ and CC₉₀/EC₉₀) values arederived.

Example 2: Infectious HCVcc Assay

Huh7.5 cells are grown in Dulbecco's modified essential media (DMEM),10% fetal bovine serum (FBS), 1% penicillin-streptomycin (pen-strep), 1%Non-essential amino acids (NEAA) in a 5% CO₂ incubator at 37° C. Huh7.5cells are seeded at 1×10⁴ cells per well into 96-well plates accordingto Southern Research Institute standard format. Test articles areserially diluted with DMEM plus 5% FBS. The diluted compound in theamount of 50 μl is mixed with equal volume of cell culture-derived HCV(HCVcc), then applied to appropriate wells in the plate. Humaninterferon alpha-2b (rIFNα-2b) and/or Sofosbuvir are included as apositive control. After 72 hr incubation at 37° C., the cells are lysedfor measurement of luciferase activity using Renilla Luciferase AssaySystem (Promega) according to manufacturer's instruction. The number ofcells in each well is determined by CytoTox-1 reagent (Promega). Testarticles are tested at 6 serial dilutions in triplicate to derive, ifapplicable, EC₅₀ and EC₉₀ (concentration inhibiting HCVcc infectivity by50% and 90%, respectively), CC₅₀ (concentration decreasing cellviability by 50%) and SI (selectivity index: CC₅₀/EC₅₀) values (Table0.1)

Prasugrel Study Study Title CC₅₀ EC₅₀ (Selectivity index) In vitro Invitro HCV 88.5 47.1 1.88 replicon assay In vitro In vitro HCV cc >1009.71 >10.3 assay

Example 3: Dosage Forms

Dosage Form A

Qty/Unit (mg) Sr. No. Ingredients 5.0 mg 10.0 mg Strength 1. Prasugrel5.00 10.00 2. Mannitol 45.00 90.00 3. Microcrystalline Cellulose 61.00122.00 4. Hypromellose 30.00 60.0 5. Croscarmellose Sodium 7.50 15.00 6.Magnesium stearate 1.50 3.00 Coating 7. Opadry II White 6.00 12.00Process:

-   -   1. Prasugrel and Mannitol, Microcrystalline cellulose,        Hvpromellose, Croscarmellose sodium was co-sifted through        suitable mesh sieve.    -   2. Pre-sifted ingredients obtained in Step 1 were loaded in        Saizoner or Rapid mixer granulator and granulated using suitable        solvent.    -   3. The granules obtained in step 2 were dried and sized through        Co-mill using suitable Screen and sieve size.    -   4. The dried and sized granules obtained in step 3 were        lubricated with pre-sifted magnesium stearate in a suitable        blender.    -   5. The lubricated granules obtained in step 4 were compressed        Coating solution was prepared by dissolving the Opadry II white        in Purified water and the compressed tablets obtained in step 6        were coated till the desired weight gain.        Dosage Form B

Qty/Unit (mg) Sr. No. Ingredients 5.0 mg 10.0 mg Strength 1. Prasugrel5.00 10.00 2. Mannitol 45.00 90.00 3. Microcrystalline Cellulose 60.00120.00 4. Hypromellose 30.00 60.00 5. Low-Substituted hydroxypropyl 7.0014.00 cellulose 6. Glyceryl dibehenate 3.00 6.00 Coating 7. Opadry IIWhite 6.00 12.00Process:

-   -   1. Prasugrel and Mannitol, Microcrystalline cellulose,        Hypromellose, Croscarmellose sodium were co-sifted through        suitable mesh sieve.    -   2. The pre-sifted ingredients obtained in step 1 were loaded in        Saizoner or Rapid mixer granulator and granulated using suitable        solvent.    -   3. The granules obtained in step 2 were dried and milled through        Co-mill using suitable Screen and sieve size.    -   4. The dried and sized granules obtained in step 3 were        lubricated with the pre-sifted magnesium stearate and in a        suitable blender.    -   5. The lubricated granules obtained in step 4 were compressed.    -   6. Opadry II white was dissolved in Purified water and the        compressed tablets obtained in step 5 were coated till the        desired weight gain.        Dosage Form C

Qty/Unit (mg) Sr. No. Ingredients 5.0 mg 10.0 mg Strength 1. Prasugrel5.0 10.0 2. HPMC K100 M CR 18.0 36.0 3. Lactose monohydrate 29.6 59.2 4.HPMC K4 M 24.0 48.0 5. Croscarmellose sodium 3.6 7.2 6. MicrocrystallineCellulose 18.0 36.0 7. Magnesium Stearate 1.8 3.6 Coating 8. Opadry IIWhite 6.00 12.00Process:

-   -   1. Prasugrel, HPMC K100 M CR, HPMC K4 M and lactose monohydrate        were cosifted through suitable mesh sieve.    -   2. Pre-sifted ingredients obtained in step 1 were loaded in a        Saizoner or Rapid mixer granulator and granulated using suitable        solvent.    -   3. The granules obtained in step 2 were dried and sized through        Co-mill using suitable Screen and sieve size.    -   4. The granules obtained in step 4 were blended with the        pre-sifted Croscarmellose sodium, Microcrystalline Cellulose and        in a suitable blender.    -   5. The blended granules obtained in step 5 were lubricated using        pre-sifted Magnesium Stearate in a suitable blender.    -   6. The lubricated granules obtained in step 6 were compressed.    -   7. Opadry II white was dissolved in Purified water and the        compressed tablets obtained in step 7 were coated till the        desired weight gain.        Dosage Form D

Sr. No. Ingredients Quantity mg/capsule 1. Prasugrel 2.5-50   2.Pregelatinized corn starch 10-150 3. Colloidal silicon dioxide 1-15 4.Magnesium stearate 3-10 5. Talc 3-10 6. Empty hard gelatin capsule 1unitProcess:

-   -   1. Prasugrel was sifted through suitable mesh sieve.    -   2. Pregelatinized corn starch, Colloidal silicon dioxide and        talc were sifted through suitable mesh sieve.    -   3. The sieved powders of step 1 & 2 were loaded in the blender        and mixed for approximately 10 minutes.    -   4. Magnesium stearate was sifted and were blended with the        powder obtained in step 3 for approximately 5 minutes    -   5. The blend obtained in step 4 were filled in the empty hard        gelatin capsule shells using a capsule filling machine.    -   Note: The processing area must be under controlled room        temperature and humidity. The limits are RH 50% to 55%,        temperature 22° C. to 27° C.        Dosage Form E

Sr. No. Ingredients Quantity mg/tablet 1. Prasugrel 2.5-50   2. Lactosemonohydrate 30-150 3. Microcrystalline cellulose (Avicel PH 101) 40-1604. Pregelatinized starch 30-60  5. Croscarmellose sodium 15-45  6.Poloxamer 188 (Pulmonic F 68) 5-20 7. Silicon dioxide colloidal 2.5-10  8. Magnesium stearate 3-10 9. Purified water q.sProcess:

-   -   1. Prasugrel, lactose, pregelatinized starch, and a portion        (one-half) of croscarmellose sodium were sifted through a        suitable mesh sieve.    -   2. Powder obtained in step 1 is mixed in a suitable mixer or        granulator for approximately 20 minutes.    -   3. Poloxamer 188 was dissolved in a sufficient quantity of        purified water for wet granulation of powder obtained in step 2.    -   4. Granules obtained in step 3 were kept in fluidized-bed dryer        until the LOD is 2% or less.    -   5. Dried granules obtained in step 4 were passed through screen        to obtain granules of the desired size (1-3 mm) and blended with        silicon dioxide (sifted through suitable mesh Sieve),        microcrystalline cellulose (pre sifted through suitable mesh        sieve), and the remaining croscarmellose sodium in an octagonal        blender for approximately 7 minutes.    -   6. Lubrication of the blend was carried out by adding magnesium        stearate (previously sifted through suitable mesh Sieve) to the        blend of step 5 and further blending for 3 minutes.    -   7. The lubricated blend obtained in step 6 was compressed into        tablets using suitable tooling using a tablet compression        machine.

The compositions and methods of the appended claims are not limited inscope by the specific compositions and methods described herein, whichare intended as illustrations of a few aspects of the claims and anycompositions and methods that are functionally equivalent are intendedto fall within the scope of the claims. Various modifications of thecompositions and methods in addition to those shown and described hereinare intended to fall within the scope of the appended claims. Further,while only certain representative compositions and method stepsdisclosed herein are specifically described, other combinations of thecompositions and method steps also are intended to fall within the scopeof the appended claims, even if not specifically recited. Thus, acombination of steps, elements, components, or constituents may beexplicitly mentioned herein or less, however, other combinations ofsteps, elements, components, and constituents are included, even thoughnot explicitly stated. The term “comprising” and variations thereof asused herein is used synonymously with the term “including” andvariations thereof and are open, non-limiting terms. Although the terms“comprising” and “including” have been used herein to describe variousembodiments, the terms “consisting essentially of” and “consisting of”can be used in place of “comprising” and “including” to provide for morespecific embodiments of the invention and are also disclosed. Other thanin the examples, or where otherwise noted, all numbers expressingquantities of ingredients, reaction conditions, and so forth used in thespecification and claims are to be understood at the very least, and notas an attempt to limit the application of the doctrine of equivalents tothe scope of the claims, to be construed in light of the number ofsignificant digits and ordinary rounding approaches.

The invention claimed is:
 1. A pharmaceutical composition comprisingprasugrel or a pharmaceutically acceptable salt thereof, at least oneother anti-hepatitis C drug, and at least one pharmaceutical excipient.2. The composition of claim 1, wherein the other anti-hepatitis C drugcomprises a recombinant Human Interferon Alfa, a nucleoside analog, adirect acting antiviral, a NS3/4A protease inhibitor, a nucleotide NS5Bpolymerase inhibitor, a NS5A inhibitors, a non-nucleoside NS5Bpolymerase inhibitors, or a combination thereof.
 3. The composition ofclaim 1, wherein the other anti-hepatitis C drug comprise peginterferon,ribavirin, daclatasvir, boceprevir, telapravir, simeprevir, sofosbuvir,dasabuvir, ombitasvir, velpatasvir, ledipasvir, paritaprevir, ritonavir,elbasvir, grazoprevir, asunaprevir, beclabuvir, or a combinationthereof.
 4. The composition of claim 1, wherein the compositioncomprises prasugrel or a pharmaceutically acceptable salt thereof, in anamount from 2-100 mg.
 5. The composition according to claim 1, whereinthe composition comprises prasugrel hydrochloride.
 6. A kit comprising(a) a composition comprising prasugrel or a pharmaceutically acceptablesalt thereof, and (b) instructions for a dosing regimen effective totreat hepatitis C, wherein the kit further comprises at least one otheranti-hepatitis C drug.
 7. The kit of claim 6, wherein the otheranti-hepatitis C drug comprises a recombinant Human Interferon Alfa, anucleoside analog, a direct acting antiviral, a NS3/4A proteaseinhibitor, a nucleotide NS5B polymerase inhibitor, a NS5A inhibitors, anon-nucleoside NS5B polymerase inhibitors, or a combination thereof. 8.The kit of claim 6, wherein the other anti-hepatitis C drug comprisepeginterferon, ribavirin, daclatasvir, boceprevir, telapravir,simeprevir, sofosbuvir, dasabuvir, ombitasvir, velpatasvir, ledipasvir,paritaprevir, ritonavir, elbasvir, grazoprevir, asunaprevir, beclabuvir,or a combination thereof.
 9. The kit of claim 6, wherein the compositioncomprises prasugrel or a pharmaceutically acceptable salt thereof in anamount from 2-100 mg.
 10. The kit of claim 6, wherein the compositioncomprises prasugrel hydrochloride.